Depression is consistently one of the top causes of morbidity and mortality, and veterans are afflicted more commonly than non-veterans. In addition, veterans are more than twice as likely to die from depression- related suicide than the general population. Despite current antidepressant medications, a disappointingly large number of patients are refractory to current treatments, all of which target similar mechanisms. Thus, new medications with novel mechanisms of action are urgently needed. Using animal models that can predict antidepressant and anti-anxiety effects in humans, we identified a novel molecule in depression and anxiety- related behaviors, the acid-sensing ion channel 1a (ASIC1A). Pharmacologically inhibiting and genetically disrupting ASIC1A in mice produced antidepressant-like effects in the forced swim test, tail suspension test, and following chronic unpredictable stress. Moreover, the effects were independent of and additive to several currently used antidepressant medications. Disrupting ASIC1A also reduced conditioned and unconditioned fear behaviors, which model post-traumatic stress disorder (PTSD) and other anxiety disorders. Together these findings suggest the exciting possibility that targeting ASIC1A will relieve depression and anxiety through a novel mechanism of action. To take full advantage of this possibility we need to know more about how ASIC1A is activated in the brain. The exquisite sensitivity of ASIC1A to low extracellular pH suggests that acidic pH might play an important signaling role. Supporting this possibility, we recently identified a novel current during synaptic transmission in the nucleus accumbens (NAc) that depended on ASIC1A and ASIC2, and was inhibited by the ASIC antagonists amiloride and psalmotoxin. Furthermore, inhibiting or genetically deleting carbonic anhydrase 4 (CA4), a key pH-buffering enzyme in the brain, increased this novel ASIC- dependent synaptic current. Finally, loss of ASIC1A and the associated current was accompanied by significant structural and functional changes at glutamatergic synapses, which we suspect may underlie the behavioral consequences of ASIC disruption. Based on these observations we hypothesize that ASICs and CA4 play key roles in depression-related synaptic physiology in the NAc and depression-related behavior. To test this hypothesis we propose to answer the following questions: 1) Do ASIC1A and ASIC2 contribute to synaptic and behavioral responses to chronic stress? 2) Does carbonic anhydrase 4 contribute to synaptic plasticity in the NAc and depression-related behavior? And, 3) can inhibiting or deleting ASIC1A reverse effects of chronic stress on depression-related behavior, and is the NAc a key site of ASIC1A action? The answers to these questions will provide important steps towards our long-term goals of better understanding the role of ASICs in brain function and behavior and learning to target these processes for therapeutic purposes.